Without limiting the scope of the invention, its background is described in connection with mechanical micronization processes or solution-based phase separation processes, as an example. Micronization procedures can modify particle size, porosity and density, and the active agent may be mixed with pharmaceutical excipients using small particle technologies to maximize delivery to the desired target for drug administration.
Delivery of a therapeutic agent to the respiratory tract is important for the treatment of local and/or systemic diseases; however, using conventional techniques for delivery of agents to the lung has proven extremely inefficient. Attempts to develop respirable micronized suspensions of poorly soluble compounds have also failed because the particles are too large to be delivered by aerosolized aqueous droplets and fail to release the drug efficiently. Using these techniques only about 10 to 20% of the agent reaches the lung due to losses to the device used to deliver the agent, loss to the mouth and throat, and exhalation.
The relative rate of absorption and residence time of the therapeutic agent must also be considered for determining the amount of therapeutic agent that reaches the site of action. Since the vast majority of the available surface area of the lung for drug delivery is located in the deep lung, delivery to the lung may best be realized with delivery of the particles to the peripheral alveoli of the deep lung. In contrast, particles deposited in the upper respiratory tract are rapidly removed by the mucociliary escalator, subsequently transported to the throat and either swallowed or removed by coughing. While delivery to the deep lung is required for efficient delivery, the particles must also be able to release their content to be effective.
Particle formation technologies may be classified as either mechanical micronization processes or solution-based phase separation processes. Mechanical micronization methods include milling techniques such as that cited in, e.g., U.S. Pat. No. 5,145,684, however, friction generated during these milling processes may lead to either thermal or mechanical degradation of the active agent. Spray drying, another common method used to micronize drug substances, can cause difficulty with respect to capturing the particles that are formed when such particles are relatively small.
Systemic fungal infections are a major cause of morbidity and mortality in the immunocompromised patient. The most common infections in this group are candidiasis and aspergillosis, especially in the case of acute invasive fungal infections. For patients infected with aspergillosis the prognosis is very poor. Mortality rates are as high as 49% for patients undergoing chemotherapy treatment for cancers such as leukemia and lymphoma, while HIV/AIDS patients have one of the highest mortality rates at 86%. The use of antimicrobial drugs (e.g., antibiotics) for the treatment of a variety of underlying medical conditions also promotes the incidence of invasive fungal infection. Lung transplant recipients are uniquely susceptible to infection due to the fact that the lungs are constantly exposed to the environment and potential pathogens. Once infection has occurred, aspergillosis accounts for 74% of fatalities in lung transplant recipients. In addition, bone marrow transplant patients comprise the highest risk group with an 87% mortality rate following infection.
The most frequently used antifungal agents are polyenes, azoles and allylamines. Of these, amphotericin B and itraconazole have the broadest spectrum of activity against the most common of fungal infections: Candida spp. and Aspergillus spp. (Meis and Verweij, 2001). In the case of itraconazole, large interindividual differences in bioavailability are observed. (Grant and Clissold, 1989) due to its poor aqueous solubility (<1 μg/mL) and subsequent poor dissolution rate. Previous research by other groups has led to the development of alternative formulations for each of these drugs. U.S. Pat. No. 4,950,477 describes a method of preventing and treating pulmonary infection by fungi using aerosolized polyenes, e.g. amphotericin B, to treat aspergillosis. United States Publication 2004/0022862 A1 describes a method for preparing small particles, wherein the particles may be suitable for in vivo delivery by an administrative route such as pulmonary. US Publication 2003/0077329 A1 describes a composition and method for preparing stable particles in a frozen aqueous matrix, wherein such particles are suitable for pulmonary delivery. USPN 2003/0072807 A1 describes solid particulate antifungal compositions for pharmaceutical use, including pulmonary formulations of such compositions (but only a brief reference to pulmonary). US Publication 2002/0102294 A1 describes aerosols comprising nanoparticle drugs, and methods of using the formulations in aerosol delivery devices. U.S. Pat. No. 6,264,922 describes nebulized aerosols containing nanoparticle dispersions. WO 90/11754 describes aerosolized azole antifungals. However, none of these references specify that a particular lung concentration for an antifungal is desired, reached or maintained over a period of time. Nor do any of these references specify that a measure of inflammatory response is desired, reached or maintained, or that a particular blood concentration of pulmonary delivered antifungal is desired, reached or maintained. US Publication 2003/0068280 A1 teaches that certain antibiotics can have a residence time of over 12 hours, but this publication does not teach or describe anything relating to antifungal agents. United States Patent Publication 2004/0176391 A1 teaches specific lung concentrations and residence times specifically for Amphotericin B.
Recent research has led to the development of, e.g., lipid-based formulations of amphotericin B and numerous examples are reported in the literature for aerosolization of lipid-based formulations of Amphotericin B to treat fungal lung infections, but this approach has disadvantages because amphotericin B is poorly water soluble and poorly permeable across biological membranes. Research has also led to the incorporation of itraconazole into a cyclodextrin complex for intravenous and oral administration; however, there are side effects and toxicities that are associated with formulations including cyclodextrins, leading to upper limits on the dosages of such formulations that may not be sufficient for treatment. Moreover, cyclodextrins would have limited applicability for patients with reduced renal function, since cyclodextrins are cleared through the kidneys. Given the broad spectrum of antifungal activity, it is clear that improvements in delivery of antifungal agents, such as itraconazole will lead to lower infection rates using prophylaxis treatment and lowered cost with more efficacious therapy. There is a clear medical need for a pulmonary formulation to supplement the currently available oral and intravenous formulations, based upon the results shown in this invention for targeted pulmonary delivery of an antifungal agent.